title: Saxagliptin Improves Glucose Tolerance but not Survival in a Murine Model of Dilated Cardiomyopathy.
abstract: Glucagon-like peptide 1 (GLP-1) agonists improve myocardial function and insulin sensitivity in the setting of chronic heart failure. Endogenously produced GLP-1 peptide (7-36) is rapidly cleaved by dipeptidyl peptidase 4 (DPP4) to the 9-36 peptide, which lacks anti-hyperglycemic activity. To elucidate the effect of increased endogenous GLP-1 during heart failure progression, the DPP4 inhibitor saxagliptin or vehicle was administered by daily oral gavage to female TG9 mice, a transgenic model of dilated cardiomyopathy, starting at day of life 42, just prior to the development of detectable contractile dysfunction. Saxagliptin treatment inhibited DPP4 activity >90% and increased GLP-1 levels 4-fold following a 2 gm/kg glucose load but did not affect fasting GLP-1 levels. There was no difference in food intake or body weight between groups. At 56 days of age, oral glucose tolerance was improved in saxagliptin-versus vehicle-treated animals (AUC0-1201340 ± 46 and 1501 ± 43 min·mmol/L, respectively, p<0.015). In contrast to the effect of a GLP-1 agonist in TG9 mice, saxagliptin had no effect on survival (80.7 ± 4.3 days) compared to vehicle-treated mice (79.6 ± 3.6 days, p = 0.46). Taken together, these data indicate that improvement in glucose tolerance is not sufficient to improve survival. Future efforts to confirm these findings in additional models of heart failure are warranted.
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis MO.
authors.forename: Arpita Kalla
authors.initials: AK
authors.lastname: Vyas
authors.forename: Lauren B
authors.initials: LB
authors.lastname: Aerni-Flessner
authors.forename: Maria A
authors.initials: MA
authors.lastname: Payne
authors.forename: Attila
authors.initials: A
authors.lastname: Kovacs
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Jay
authors.forename: Paul W
authors.initials: PW
authors.lastname: Hruz
keywords: cardiac function; glucose transport; incretin hormone; insulin sensitivity; mouse model